Summary
Background HASPIN, a mitotic kinase for Histone H3, is a promising target for anti-cancer therapy. However, as HASPIN is an atypical kinase with low similarity to eukaryotic protein kinases, development of a HASPIN inhibitor from the conventional pharmacophore of kinase inhibitors would be technically challenging.
Methods Chemical modifications of a cytotoxic 4’-thioadenosine analogue with high genotoxicity and multiple kinomescan profiles were performed to produce a novel non-genotoxic kinase inhibitor, LJ4827. The mode of action of this inhibitor with clear anti-cancer activity was inferred based on transcriptomic and chemical similarity to known drugs.
Results The specificity and potency of LJ4827 as a HASPIN inhibitor were validated by in vitro kinase screening and subsequent X-ray crystallography. As predicted, LJ4827 treatment delayed mitosis by clear inhibition of the recruitment of Aurora B at the centromere in cancer cells, without a genotoxic response. Through transcriptome analysis of lung cancer patients, PLK1 was predicted as a druggable synergistic partner to complement HASPIN inhibition. Cotreatment with the PLK1 inhibitor BI2536 and LJ4827 led to pronounced cytotoxicity of lung cancers in vitro and in vivo.
Conclusion Simultaneous inhibition of both HASPIN and PLK1 is a promising therapeutic strategy for lung cancers.
Competing Interest Statement
The authors have declared no competing interest.
List of Abbreviations
- HASPIN
- Haploid Germ Cell□Specific Nuclear Protein Kinase
- GSG2
- Germ cell-specific gene 2 protein
- CPC
- Chromosome passenger complex
- MoA
- Mode of action
- SMILES
- Simplified Molecular Input Line Entry System
- AdK
- Adenosine kinase
- 5ITU
- 5-iodotubercidin
- FUCCI
- Fluorescence ubiquitination cell cycle indicator
- hMSCs
- Human mesenchymal stem cells
- AMSES
- Active mitosis signature enrichment score
- TCGA
- The cancer genome atlas
- CMap
- Connectivity Map